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In the European Union, bioequivalence (BE) for narrow therapeutic index (NTI) drugs is currently demonstrated when the 90% confidence interval for the ratio of the population geometric means of the test and reference products for AUC, and in some cases for Cmax, falls within the acceptance range of 90.00% to 111.11%. However, meeting this requirement results in an increased difficulty of demonstrating BE and a need for clinical trials with larger subject sample sizes, especially for medium-to-high variability drugs. To address this challenge, a scaled average BE based on the reference product within-subject variability for narrowing the acceptance range of NTI drugs was recently proposed. However, this approach showed increased type I error (T1E), especially close to the cut-off point between the unscaled and scaled portions of the method. Based on simulations, this limitation can be overcome by predefining the protocol the path to be followed: either the fixed 90.00–111.11% acceptance range approach or the previously proposed scaled average BE approach with a slight adjustment of the one-sided significance level α to 0.042 for a 2 × 3 × 3 partial replicate design and without a lower cut-off point. This results in a mixed approach allowing to reduce the sample size whilst not inflating the T1E. [ABSTRACT FROM AUTHOR]

In the European Union, bioequivalence (BE) for narrow therapeutic index (NTI) drugs is currently demonstrated when the 90% confidence interval for the ratio of the population geometric means of the test and reference products for AUC, and in some cases for Cmax, falls within the acceptance range of 90.00% to 111.11%. However, meeting this requirement results in an increased difficulty of demonstrating BE and a need for clinical trials with larger subject sample sizes, especially for medium-to-high variability drugs. To address this challenge, a scaled average BE based on the reference product within-subject variability for narrowing the acceptance range of NTI drugs was recently proposed. However, this approach showed increased type I error (T1E), especially close to the cut-off point between the unscaled and scaled portions of the method. Based on simulations, this limitation can be overcome by predefining the protocol the path to be followed: either the fixed 90.00–111.11% acceptance range approach or the previously proposed scaled average BE approach with a slight adjustment of the one-sided significance level α to 0.042 for a 2 × 3 × 3 partial replicate design and without a lower cut-off point. This results in a mixed approach allowing to reduce the sample size whilst not inflating the T1E.

This work presents, for the first time, the voltammetric behavior of clonidine (CLO) drug and its determination, using an unmodified glassy carbon electrode (GCE). CLO exhibited only an irreversible oxidation process on the GCE, with peak potential at +0.85 V in pH 12 (vs Ag/AgCl). CLO oxidation process is pH‐dependent and the electrochemical mechanisms on the GCE were proposed in acidic and basic medium. The determination of CLO was optimized in 0.1 mol L−1 phosphate buffer solution at pH 12.0 using differential pulse voltammetry (DPV), which provides a good linear range (0.65 to 106.00 μmol L−1) and low theoretical limit of detection (0.14 μmol L−1) for the quality control of this drug in pharmaceutical samples. In addition, stable responses of CLO at the GCE were obtained in the same day (RSD = 3.4 %; n = 5) and different days (RSD = 2.0 %; n = 3). Moreover, the determination of CLO in a pharmaceutical formulation using the proposed GCE‐DPV method presented good accuracy, since the recovery was close to 100 % and the dosing result was in agreement with an official method (HPLC‐UV). The proposed method demonstrates a good analytical performance for CLO determination in pharmaceutical samples, providing a faster, simpler and lower‐cost alternative for quality control of CLO than other reported methods. [ABSTRACT FROM AUTHOR]

[Display omitted] With the growing interest in environmentally friendly and personalized medicines, new concept for combining three-dimensional printing (3DP) with natural-based biomaterials derived from agro-food wastes has emerged. This approach provides sustainable solutions for agricultural waste management and potential for developing of novel pharmaceutical products with tunable characteristics. This work demonstrated the feasibility of fabricating personalized theophylline films with four different structures (Full, Grid, Star, and Hilbert) using syringe extrusion 3DP and carboxymethyl cellulose (CMC) derived from durian rind wastes. Our findings suggested that all the CMC-based inks with shear thinning properties capable of being extruded smoothly through a small nozzle could potentially be used to fabricate the films with various complex printing patterns and high structural fidelity. The results also demonstrated that the film characteristics and release profiles could be easily modified by simply changing the slicing parameters (e.g., infill density and printing pattern). Amongst all formulations, Grid film, which was 3D-printed with 40 % infill and a grid pattern, demonstrated a highly porous structure with high total pore volume. The voids between printing layers in Grid film increased theophylline release (up to 90 % in 45 min) through improved wetting and water penetration. All findings in this study provide significant insight into how to modify film characteristics simply by digitally changing the printing pattern in slicer software without creating a new CAD model. This approach could help to simplify the 3DP process so that non-specialist users can easily implement it in community pharmacies or hospital on demand. [ABSTRACT FROM AUTHOR]

The prescription of generic drugs represents one of the main cost-containment strategies of health systems, aimed at reducing pharmaceutical expenditure. In this context, most regulatory authorities encourage or obligate dispensing generic drugs because they are far less expensive than their brand-name alternatives. However, drug substitution can be critical in particular situations, such as the use of drugs with a narrow therapeutic index (NTI). Moreover, generics cannot automatically be considered bioequivalent with each other due to the biocreep phenomenon. In Italy, the regulatory authority has established the Transparency Lists which include the medications that will be automatically substituted for brand-name drugs, except in exceptional cases. This is a useful tool to guide prescribers and guarantee pharmaceutical sustainability, but it does not consider the biocreep phenomenon. [ABSTRACT FROM AUTHOR]

We report two clinical cases assessed in our minor ailment service presenting with symptoms suggestive of common digestive disorders. Both patients were treated with narrow therapeutic index drugs (lithium carbonate and digoxin, respectively). In both cases, medication analysis revealed that referred symptoms might be elicited by these drugs: abdominal discomfort is a frequent adverse reaction in long term treatments with lithium carbonate while in the case of digoxin symptomatology was found to be accompanied by bradycardia. Thus, we propose two different pharmaceutical interventions, one being an urgent general practitioner referral. Pharmacotherapy assessment during minor ailment service, focused on narrow therapeutic index drugs, is a key point in discriminating minor ailments from potential life-threatening situations. [ABSTRACT FROM AUTHOR]

For the first time, a comprehensive review is presented on the quantitative determination of narrow therapeutic index drugs (NTIDs) by nano optical and electrochemical sensors and biosensors. NTIDs have a narrow index between their effective doses and those at which they produce adverse toxic effects. Therefore, accurate determination of these drugs is very important for clinicians to provide a clear judgment about drug therapy for patients. Routine analytical techniques have limitations such as being expensive, laborious, and time-consuming, and need a skilled user and therefore the nano/(bio)sensing technology leads to high interest. [ABSTRACT FROM AUTHOR]

Reducing sugars causes confirmatory alterations in albumin structure by the nonenzymatic glycation of the amino group of serum albumin. In this study, glucose and its hazardous metabolic products like glyoxal and methylglyoxal were incubated with bovine serum albumin (BSA). The confirmational changes in BSA molecule's structure by glycating substances was investigated using a variety of spectroscopic methods, including deconvolutionFourier Transform Infra-red (FT-IR) spectroscopy, fluorescence spectroscopy, UV spectroscopy and circular dichroism (CD) spectroscopy. Dynamic fluorescence quenching was observed in the case of glucose, while static quenching was observed in the case of methyl glyoxal and glyoxal. Similarly, employing deconvolution FT-IR spectroscopy and CD spectroscopy for determination of change in secondary structures in terms signature of α-helix, β-turn, β-sheet and random coil modifications. Destabilization or unfolding of the albumin structure, due to the disruption of the hydrogen bonding pattern that stabilizes the albumin manifold, causes a 25-50% reduction in α-helix and a 2-fold increase in β-sheet and turns in glycated BSA. The competitive displacement interaction studies with warfarin were performed using the ultrafiltration technique and quantitative determination of free drug in ultrafiltrate using LC-MS/MS. The binding of carbamazepine (CBZ) or its active metabolite to proteins was unaffected by the glycation of BSA with glucose and methyl glyoxal. Nevertheless, with glyoxal-modified BSA, it changed the binding of selected analytes significantly. Based on in vitro observations and results, it could be anticipated that the serum CBZ concentration variation may be worsened in uncontrolled diabetes circumstances, with an overall variance of 30-40% possible.Communicated by Ramaswamy H. Sarma.

Drug innovations can outpace regulatory drug approval processes designed to control risk, creating heterogeneous risks among approved drugs. This paper estimates a price model for risky narrow therapeutic index (NTI) drugs. The traditional generic approval process has been criticized as insufficient to guarantee therapeutic equivalence in NTI drugs, leading to higher risks of toxicity or ineffectiveness when a patient switches from a brand-name version of an NTI to a generic version, or between generic versions. Using data from the Medical Expenditure Panel Survey, this paper finds evidence of a significant price penalty for NTI drugs. The paper also finds a smaller gap between brand-name and generic prices for NTI drugs than for non-NTI drugs, consistent with costly switching. An analysis of drug consumption bundles also supports this theory. These results show that despite the many information asymmetries and agency issues in the pharmaceutical market, there is evidence of sensitivity to risk in price and consumption behavior. [ABSTRACT FROM AUTHOR]

Abstract: The use of multiple‐pulse amperometry (MPA) for the determination of narrow therapeutic index (NTI) drugs using batch injection analysis (BIA) with carbon screen‐printed electrodes (SPE) is proposed, seeking to develop a practical and low‐cost analysis kit for application in routine quality control of these drugs. The electrochemical behaviors of aminophylline, carbamazepine, clindamycin, colchicine, minoxidil, prazosin, procainamide, theophylline, warfarin and verapamil were evaluated in different electrolytes, but just one, the 0.1 mol L−1 phosphate buffer, pH 7.0, was chosen for determination of all the analytes. The amperometric detection was optimized as a function of the best oxidation potential for carbon SPE for each analyte, which was in a range from 0.7 to 1.1 V. The injection conditions were determined as a function of the velocity and the volume injected by the BIA system, which were 92.5 μL s−1 and 100 μL, respectively. Under these conditions, a good repeatability (RSD<3 %), high analytical frequency (>215 determinations per hour), large linear ranges and low LOD (<0.42 μmol L−1) for all the NTI drugs were obtained. Furthermore, the proposed method provided an easy qualitative analysis of the investigated analytes using MPA detection. The addition‐recovery studies in pharmaceutical samples containing NTI drugs and the comparison with official methods showed that the proposed analysis Kit is a very fast, simple and efficient alternative for quantification of these analytes. [ABSTRACT FROM AUTHOR]

Objectives: To identify and categorize types of Drug Related Problems (DRPs), assess various risk factors for developing DRPs and delineate if drugs with narrow therapeutic index or non-narrow therapeutic index drugs cause greater number of DRPs. Methods: Patients from General Medicine, Surgery, Psychiatry, Cardiac and Intensive Care Unit (ICU) departments of a tertiary care teaching hospital were included. Data was collected prospectively over eight months from medical history, medication charts, case notes and laboratory data. Only those patients prescribed at least five drugs were included. Pediatric and Oncology patients and pregnant women were excluded from the study. Narrow therapeutic index (NTI) drugs (Insulin, digoxin, warfarin, levothyroxine, aminoglycoside antibiotics, carbamazepine, lithium and phenytoin) were compared with non NTI-drugs to delineate patterns of DRPs between both groups. Results: A total of 200 patients were enrolled in the study, and 172 DRPs were identified. The most common DRPs were: drug interactions (63%), inappropriate drug use (10.5%) and adverse drug reactions (10.5%). Polypharmacy and duration of hospitalization were established as significant risk factors for developing DRPs. NTI-drugs had a greater risk of developing DRPs (0.22) versus non-NTI drugs (0.08). Two categories of DRPs were found to be more significantly associated with NTI-drugs: ADRs and inappropriate drug use. Conclusion: While ADR and inappropriate drug use were more common with NTI-drugs, in clinical practice other non NTI-drugs: Anti-psychotic drugs (quetiapine, amisulpride etc.) and NSAIDs (aspirin) showed a high tendency for interactions and needed frequent monitoring. [ABSTRACT FROM AUTHOR]

Background: Tablet splitting or pill splitting frequently occurs in daily medical practice. For drugs with special pharmacokinetic characters, such as drugs with narrow therapeutic index (NTI), unequal split tablets might lead to erroneous dose titration and it even cause toxicity.Objective: The aim of this study was to investigate the frequency of prescribing split NTI drugs at ambulatory setting in Taiwan.Setting: A population-based retrospective study was conducted using the National Health Insurance Research Database in Taiwan. All ambulatory visits were analyzed from the longitudinal cohort datasets of the National Health Insurance Research Database.Methods: The details of ambulatory prescriptions containing NTI drugs were extracted by using the claims datasets of one million beneficiaries from National Healthcare Insurance Research Database in 2010 in Taiwan. The analyses were stratified by dosage form, patient age and the number of prescribed tablets in a single dose for each NTI drugs. Main outcome measures Number and distinct dosage forms of available NTI drug items in Taiwan, number of prescriptions involved split NTI drugs, and number of patients received split NTI drugs.Results: A total of 148,548 patients had received 512,398 prescriptions of NTI drugs and 41.8 % (n = 62,121) of patients had received 36.3 % (n = 185,936) of NTI drug prescriptions in form of split tablets. The percentage of splitting was highest in digoxin prescriptions (81.0 %), followed by warfarin (72.0 %). In the elderly patients, split tablets were very prevalent with digoxin (82.4 %) and warfarin (84.5 %).Conclusion: NTI drugs were frequently prescribed to be taken in split forms in Taiwan. Interventions may be needed to provide effective and convenient NTI drug use. Further studies are needed to evaluate the clinical outcome of inappropriate split NTI drugs. [ABSTRACT FROM AUTHOR]

The principles for assessing therapeutic equivalence based on bioequivalence studies as accepted in Russia are significantly different from those adopted abroad, in particular with respect to drugs with narrow therapeutic indices (NTI). Certification of these drugs based on bioequivalence studies with commonly recognized limits is unacceptable in practice because drugs in this concentration range can cause serious adverse side effects and be more dangerous than the reference drug. The situation becomes especially critical when the reference drug is replaced by a generic. This circumstance creates the need to develop stricter regulations for NTI drugs. This article analyzes possible approaches to planning bioequivalence investigations for NTI drugs as adopted by leading world regulatory institutions in order to harmonize them with bioequivalence studies of NTI drugs in the Russian Federation. General recommendations for planning bioequivalence studies of NTI drugs were formulated based on the analysis. [ABSTRACT FROM AUTHOR]

We report two clinical cases assessed in our minor ailment service presenting with symptoms suggestive of common digestive disorders. Both patients were treated with narrow therapeutic index drugs (lithium carbonate and digoxin, respectively). In both cases, medication analysis revealed that referred symptoms might be elicited by these drugs: abdominal discomfort is a frequent adverse reaction in long term treatments with lithium carbonate while in the case of digoxin symptomatology was found to be accompanied by bradycardia. Thus, we propose two different pharmaceutical interventions, one being an urgent general practitioner referral. Pharmacotherapy assessment during minor ailment service, focused on narrow therapeutic index drugs, is a key point in discriminating minor ailments from potential life-threatening situations., (Copyright SEFAC. Sociedad Española de Farmacia Clínica, Familiar y Comunitaria. This article is available from url https://www.farmaceuticoscomunitarios.org/.)

Abstract: Generics are usually considered to exhibit comparable in vivo properties in terms of efficacy and safety and for this reason are intended to be interchangeable with the reference product. The aim of this study is to provide a quantitative picture of the switchability problem between two generics and to introduce the concept of conditional probability of bioequivalence (BE) acceptance. Monte Carlo simulations were performed to examine all possible relationships between the tested products. Four types of percent BE acceptances are defined and evaluated: (a) %BA1, when generic T1 is compared to the R product, (b) %BA2, in cases of comparison of generic T2 with the R product, (c) %BA21, when generic T2 is compared to another generic T1, and finally (d) %BA21C which is the conditional probability of percent bioequivalence acceptance of generic T2 versus another generic T1 given that both T1 and T2 are declared bioequivalent to the same R formulation. The simulations were expanded to study concomitantly the performance of T1 and T2 when compared to the same R formulation. In each case, the 2×2 cross-over design was used and evaluation of BE was based on the classic BE limits (0.80–1.25) and the stricter BE limits (0.90–1.11) for narrow therapeutic index (NTI) drugs. A number of 24 and 48 subjects were assumed to participate in the simulated trials, while the coefficient of variation for the within-subject variability (CVw) was 20% and 40%. A number 40,000 BE trials were simulated under each condition. The T1/R and T2/R ratios ranged from 0.80 to 1.25 using a step of 0.05. Even though two generics (T1 and T2) can be declared bioequivalent to the same R product, this does not ensure that they are always mutually bioequivalent. On the contrary, two generic products which differ substantially from the R product can still have a high probability to be truly interchangeable. The two generics (T1 and T2) can be switched from one to another when the T1/R and T2/R ratios are close to the same value, the CVw of the drug is low, and each BE study of T1–R and T2–R was conducted using a relatively large number of subjects. In the same context, two generic NTI drugs which differ more than 10% from the R product can still be declared bioequivalent to one another depending on the relative T1/R and T2/R ratios. Switchability between generics assessed at the 0.90–1.11 interval is safer, but not always ensured. [Copyright &y& Elsevier]

A simulation-based comparison study on the relative merits of dose-control trials (DCTs) with exposure–response analysis versus concentration-control trials (CCTs) for drugs with narrow therapeutic index showed that DCT designs are more informative about the exposure–response relationship. The authors revisit the question employing optimal design methodology and propose strategies for designing ethically attractive trials for these drugs, balancing between individual–collective risk and informativeness. An optimal study was performed considering a hypothetical immunosuppressant agent with 2 clinical end points. Different scenarios were optimized applying cost-based designs (unwanted events vs number of subjects/trial or maximal individual risk). Dose/exposure targets and number of subjects per trial/arm were optimized. Prior information inclusion on baseline risks was evaluated. DCTs were more informative, needing smaller studies to provide the same information as CCTs. Using the number of unwanted events—rather than subjects—as cost resulted in ethically more attractive designs. Including prior baseline risk information reduced the number of subject/events and allowed the use of targets closer to the optimal. Designing dose-finding trials for some narrow therapeutic index drugs may be improved by using DCTs with exposure–response analysis, cost-based designs, prior information, and optimal design analysis providing information on the ethical trade-off between individual risk and information gain. [ABSTRACT FROM PUBLISHER]

Objective: To generate patient-centered, evidence-based decision support tools and compile resources that will assist pharmacists in prescription drug product substitution activities and related communication, and to present the resulting tools and resources. Data Sources: Food and Drug Administration (FDA) publications, data, and communication; peer-reviewed literature; interviews with pharmacists; structured discussions with members of the project Advisory Board; and author's own knowledge and records of events. Summary: A decision whether to substitute an alternative product for a prescribed medication is a clinically based process that must be grounded in appropriate medical evidence, therapeutic equivalence information, financial factors, and consideration of how the substitution will impact the patient. Product substitution decisions are influenced by therapeutic issues, legal matters, patient-centered concerns, and pharmacy practice factors, including work flow, supply issues, access to current resources, and misperceptions about database information. While generic substitution is clearly defined in many cases, some medication categories require special consideration, i.e., critical dose and narrow therapeutic index drugs, products with special release mechanisms, bioengineered protein products, many hormonal products, older drugs marketed before 1938 that were not subject to FDA approval, and others with limited bioequivalence data. In response to reports of the challenges pharmacists face when determining the appropriateness of product substitution and in support of their interdisciplinary efforts to improve medication use, the American Pharmacists Association (APhA) convened an advisory board to create the decision support tool featured in this article. Conclusion: The U.S. health care system and patients rely on pharmacists as medication use experts to ensure that prescription drug product substitutions are appropriate. Pharmacists must be able to efficiently determine therapeutic equivalence, identify situations where further research is required, have access to timely resources for gathering information, and effectively communicate with patients and physicians about substitution issues. The prescription drug product substitution tool and related resources presented are intended to assist pharmacists in making and communicating clinically sound product substitution decisions that are patient centered, evidence based, consistent with state and federal laws and regulations, and reflective of the realities of health care today. [ABSTRACT FROM AUTHOR]

Despite potency against a variety of cancers in preclinical systems, melittin (MEL), a major peptide in bee venom, exhibits non-specific toxicity, severe hemolytic activity, and poor pharmacological properties. Therefore, its advancement in the clinical translation system has been limited to early-stage trials. Herein, we report a biohybrid involving a bottlebrush-architectured poly(ethylene glycol) (PEG) and MEL. Termed pacMEL, the conjugate consists of a high-density PEG arrangement, which provides MEL with steric inhibition against protein access, while the high molecular weight of pacMEL substantially enhances plasma pharmacokinetics with a ∼10-fold increase in the area under the curve (AUC ∞ ) compared to free MEL. pacMEL also significantly reduces hepatic damage and unwanted innate immune response and all but eliminated hemolytic activities of MEL. Importantly, pacMEL passively accumulates at subcutaneously inoculated tumor sites and exhibits stronger tumor-suppressive activity than molecular MEL. Collectively, pacMEL makes MEL a safer and more appealing drug candidate.